tbuckley/cabot-search huggingface dataset:
Programmed death‐ligand 1 expression on CD22‐specific chimeric antigen receptor‐modified T cells weakens antitumor potential
Authors: Jie Liu, Fengjuan Zhang, Jian Yu, Qi Zhao
Journal: MedComm (2022)

The molecules of programmed cell death protein-1 (PD-1) and ligand-1 (PD-L1) become new therapeutic targets for cancer therapy. Although tumor-expressed PD-L1 molecule is frequently dispensable for checkpoint blockade in some cancer patients, recent studies suggest that T cell-expressed PD-L1 molecule might play a crucial role in antitumor immunity. Here, to investigate CD22 chimeric antigen receptor (CAR)-T cell therapy, we have generated the different CD22 CAR-T constructs. We noticed that tumor cells induced PD-L1 expression on the surface of CD22 CAR-T cells. The induced PD-L1 might limit immunogenic responses of CAR-T cells. T cell-expressed PD-L1 leads to a suppressive signal by PD-1/PD-L1 engagement of CD22 CAR-T cells. Meanwhile, PD-L1 suppresses CD22 CAR-T cell differentiation into memory T cells and negatively affected secretions of several essential cytokines, such as interleukin-2 (IL-2) and tumor necrosis factor (TNF)-α. We further observed that anti-PD-L1 monoclonal antibodies rescued cytokine secretion of CD22 CAR-T cells rather than anti-PD-1 monoclonal antibodies. Our current studies provide a potential mechanism to understand the functions and roles of T cell-expressed PD-L1 in tumor microenvironment. These results will encourage the physicians to re-recognize the important roles of PD-L1 in cancer immunotherapy studies and provide the helpful guidance for clinical operation of PD-L1 inhibition drugs.
Correction: School performance in Danish children exposed to maternal type 1 diabetes in utero: A nationwide retrospective cohort study
Authors: Anne Lærke Spangmose, Niels Skipper, Sine Knorr, Tina Wullum Gundersen, Rikke Beck Jensen, Peter Damm, Erik Lykke Mortensen, Anja Pinborg, Jannet Svensson, Tine Dalsgaard Clausen
Journal: PLoS Medicine (2022)

[This corrects the article DOI: 10.1371/journal.pmed.1003977.].
Association of Late Preterm Birth and Size for Gestational Age With Cardiometabolic Risk in Childhood
Authors: Yulika Yoshida-Montezuma, Branavan Sivapathasundaram, Hilary K. Brown, Charles Keown-Stoneman, Russell J. de Souza, Teresa To, Cornelia M. Borkhoff, Catherine S. Birken, Jonathon L. Maguire, Laura N. Anderson
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The long-term cardiometabolic consequences of late preterm birth (34-36 weeks' gestation) are not well understood. <h3>Objective</h3> To assess whether late preterm birth and size for gestational age are associated with cardiometabolic risk (CMR) in childhood. <h3>Design, Setting, and Participants</h3> This retrospective cohort study included 1742 children born in Ontario, Canada, between April 1, 2006, and September 30, 2014, and followed up until September 30, 2019. Data from children enrolled in The Applied Research Group for Kids (TARGet Kids!) primary care practice–based research network were linked to administrative health care data at ICES (formerly known as the Institute for Clinical Evaluative Sciences). Participants were excluded if they had conditions affecting growth (eg, failure to thrive or cystic fibrosis), any acute or chronic conditions (other than asthma and high-functioning autism), severe developmental delay, or families who were unable to communicate in English. <h3>Exposures</h3> Late preterm birth, gestational age as a continuous measure, and size for gestational age. <h3>Main Outcomes and Measures</h3> The primary outcome was composite CMR score (overall age- and sex-standardized<i>z</i>score of CMR components, including waist circumference, log triglyceride level, glucose level, systolic blood pressure, and high-density lipoprotein cholesterol level). Secondary outcomes were the individual CMR components. Multivariable linear regression analysis was used to separately evaluate the associations of late preterm birth, continuous gestational age, and size for gestational age with CMR at ages 3 to 12 years. <h3>Results</h3> Among 2440 eligible children, 1742 (mean [SD] age, 5.6 [2.2] years; 951 boys [54.6%]) were included in the final cohort. Overall, 87 children (5.0%) were born moderately preterm (&lt;34 weeks' gestation), 145 (8.3%) were born late preterm (34-36 weeks' gestation), 455 (26.1%) were born early term (37-38 weeks' gestation), and 1055 (60.6%) were born full term (≥39 weeks' gestation). Compared with children born full term, those born moderately preterm (adjusted β = 0.50; 95% CI, 0.24-0.75) and late preterm (adjusted β = 0.27; 95% CI, 0.06-0.47) had higher CMR scores. Each additional gestational week was associated with a 0.06 U (adjusted β; 95% CI, –0.08 to –0.03 U) decrease in CMR. <h3>Conclusions and Relevance</h3> In this study, children born late preterm and moderately preterm had higher CMR. These results suggest that screening and early-life interventions for these children may prevent cardiometabolic outcomes.
What’s the best model to predict eGFR loss at 1 year after minimally invasive partial nephrectomy?
Authors: F. Crocerossa, U. Capitanio, A. Minervini, U. Carbonara, D. Eun, F. Cantiello, R. Damiano, F. Porpiglia, R. Autorino
Journal: European Urology (2022)
Immune checkpoint inhibitor–induced diabetes mellitus across NCI trials.
Authors: Zoe E. Quandt, Vanessa Hill, Joe E. Dib, Jason Burian, Sapir Tessler, Abdul Rafeh Naqash, Mark S Anderson, Megan Othus, Elad Sharon
Journal: Journal of Clinical Oncology (2022)

2668 Background: Immune checkpoint inhibitors (CPI) are known to rarely cause new onset diabetes (CPI DM). While rare, this adverse event is quite challenging for patients and clinicians to manage. Therefore, it is important to identify risk factors and clinical characteristics. This is the first comprehensive, multi-institutional study of CPI-DM across multiple agents and cancer types. Methods: The NCI Cancer Therapy Program (CTEP) database of adverse events (AEs) was queried for AEs related to diabetes (Grade 3 or 4 hyperglycemia, Acidosis including Diabetic Ketoacidosis (DKA), glucose intolerance and diabetes mellitus) among 6,925 patients who had been treated with a PD-(L)1 inhibitor alone or in combination from 6/2015 to 12/2019. Each AE report was reviewed and classified as due to CPI DM, new onset type 2 diabetes mellitus (T2DM), T2DM exacerbation without medication non-compliance, existing DM with medication non-compliance, or association with steroids (SDM). CPI DM was diagnosed based on: evidence of insulin deficiency either through presentation in DKA or low c-peptide with need for long term basal bolus insulin to maintain euglycemia and/or positive islet autoantibodies. Results: In total, there were 82 cases with at least one of these AEs; 41 had CPI-DM, 22 had SDM, 1 had new T2DM, 4 had T2DM exacerbation, 3 had medication noncompliance and 11 had acidosis not attributable to diabetes or had insufficient data. After excluding non-hyperglycemic acidosis, 57.8% had CPI-DM. Furthermore, if not on steroids and in good compliance with diabetes medications, 89.1% had CPI-DM. The incidence of CPI-DM was 0.59%; it was most common on combination PD-1/CTLA-4 inhibitor therapy (0.85%, 15/1767), followed by PD-(L)1 inhibitor monotherapy (0.54%, 18/3354), followed by CPIs combined with additional agents including chemotherapy and targeted agents (0.44%, 8/1804)(p = 0.25). Hospitalization was required for 87.5% of CPI-DM cases with 74.3% of those requiring an inpatient endocrine consult. All but one CPI-DM case had an endocrine consult at as either an inpatient or outpatient. Conclusions: While rare, this cohort shows the large health care burden of CPI-DM and that any hyperglycemia, and especially marked hyperglycemia, should be treated as CPI-DM until proven otherwise. [Table: see text]
Telemedicine adoption and utilization among financially distressed patients with cancer during the COVID-19 pandemic: Insights from a longitudinal nationwide survey.
Authors: Abbas Hassan, Carrie K. Chu, Jun Liu, Rebekah Angove, Gabrielle Betty Rocque, Kathleen D. Gallagher, Adeyiza O. Momoh, Nicole E. Caston, Courtney Williams, Stephanie B. Wheeler, Charles E. Butler, Anaeze Chidiebele Offodile
Journal: Journal of Clinical Oncology (2022)

1596 Background: Telemedicine use during the COVID-19 pandemic among financially distressed patients with cancer, with respect to the determinants of adoption and patterns of utilization, has yet to be delineated. We sought to systematically characterize telemedicine utilization in financially distressed patients with cancer during the COVID-19 pandemic. Methods: We conducted an analysis of survey data assessing the use of telemedicine in patients with cancer during the COVID-19 pandemic collected by Patient Advocate Foundation (PAF) from May 2020 to December 2020. Primary study outcome was telemedicine utilization rate. Secondary outcomes were independent predictors of telemedicine utilization patterns, volume, and utilization preferences. Multivariate and poisson regression analyses were used to identify predictive factors. Results: Of the 1,390 respondents, 627 completed two survey waves and were included in this study. Telemedicine adoption during the pandemic was reported by 67% of patients, with most (63%) preferring video visits. Younger age (odds ratio, 6.07; 95% CI, 1.47-25.1), and higher comorbidities (odds ratio, 1.79; 95% CI, 1.13-2.65) were independent predictors associated with telemedicine adoption. Younger age (19-35 yrs.) (incidence rate ratios [IRR], 1.78; 95%CI, 24-115%) and higher comorbidities (≥3) (IRR; 1.36; 95%CI, 20-55%) were independent predictors associated with higher utilization volume. As area deprivation index increased by 10 units, the number of visits decreased by 3% (IRR 1.03, 95%CI, 1.03-1.05). Conclusions: The rapid adoption of telemedicine may exacerbate existing inequities, particularly among vulnerable financially under-resourced patients with cancer. Policy-level interventions are needed for the equitable and efficient provision of this service.
HGG-53. "Profile of High Grade Gliomas and Diffuse Intrinsic Pontine Gliomas in Greek Pediatric Patients: an 8-year Single Institution's experience"
Authors: Kleoniki Roka, Maria Filippidou, Antonia Vlachou, Maria Gavra, Dimitrios Panagopoulos, Georgios Markogiannakis, Eleftheria Kokkinou, Aikaterini Alexopoulou, Maria Chasiotou, Georgios Sfakianos, Roser Pons, Kalliopi Stefanaki, Antonis Kattamis
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND/OBJECTIVES: Aggressive clinical and biological behavior, high morbidity and mortality are the main characteristics of pediatric high-grade-gliomas (HGG). Our aim was to study patients (pts) with ΗGG or diffuse-intrinsic-pontine-glioma (DIPG), diagnosed in the largest pediatric neurooncology Center in Greece. DESIGN-METHODS: We performed a retrospective-review of newly-diagnosed pts with HGG or DIPG during 2014-2021. Gender, age, location, resectability, type of surgery, histological and molecular characteristics, management and outcome were analyzed. RESULTS: During the study-period, 38pts (18females), median age:9.35y(range:3days-16.9y), were diagnosed in our center. The most common tumor-location were pons (17/38 pts) and parietal lobe (11/38 pts). DIPG based on imaging-studies was diagnosed in 16pts. Surgical approach was performed in 32pts (VP-shunt insertion:8, biopsy:12, partial resection:6, subtotal: 6). In 23pts(5 brainstem-tumors) a histological-diagnosis was feasible. Astrocytoma grIV was found in 60.8% and grΙΙΙ in 26.1%(14 and 6 respectively). Of notice, 3 additional pts with histological findings of low-grade(2grII and 1gr1), were upgraded in grIV after molecular-studies and DNA-methylation analysis. Furthermore, 17.3% of the pts (4/23, 3 located in the midline) carried a Η3Κ27Μ-mutation (diffuse midline glioma, DMG), 17.3% a Η3F3A-mutation and 8.6% showed ΕGFR-overexpression. All patients&amp;gt;3years of age were treated upfront according to HIT-HGG2013 with radiotherapy-temozolomide (29/32pts). In 5DIPG pts, reirradiation after disease-progression resulted in temporary symptomatic improvement. HGG-pts upon progression were treated with bevacizumab-irinotecan. Of the 38pts, 6pts elected to receive treatment in other countries. Overall-survival was 75.1%,15.1% and 3.7% at 1,2 and 3 years post-diagnosis respectively. Patients with DIPG/ DMG and non-midline HGG had a median overall-survival of 1.10 years and1.34 years, respectively. CONCLUSIONS: The experience of our unit concurs with worldwide published series and shows that pediatric HGG and DIPG have a dismal prognosis. Re-irradiation may offer short survival prolongation. ASKNOWLEDGEMENTS: Authors asknowledge the contribution of KiTZ-Heidelberg in molecular diagnostics through collaboration with ACCC.
Genomic co-genotype classification and clinical prognosis in Ewing sarcoma.
Authors: Yang You, Xi Guo, Rongyuan Zhuang, Wei Li, Chenlu Zhang, Zhiming Wang, Feng Shen, Qiwen Zhou, Zhengqing Song, Yong Zhang, Weiqi Lu, Zhengzeng Jiang, Xiaoyu Zhou, Ying Sun, Yuhong Zhou, Yuan Ji
Journal: Journal of Clinical Oncology (2022)

e23532 Background: Ewing sarcoma is a highly aggressive round cell mesenchymal tumor that commonly occurs in children and young adults. It is molecularly characterized by chromosomal translocations, most commonly t (11;22), resulting in the abnormal EWSR1-FLI1 fusion. In addition to EWSR1-FLI1, patients may have other genomic variants that can be used for risk stratification. In the present study, we retrospectively investigated the association between co-variant genes and prognosis in patients with Ewing sarcoma. Methods: From 2019 to 2021, 10 patients with Ewing sarcoma were enrolled in the study, and their standard first-line treatment consisted of five-drug regimen chemotherapy including vincristine, doxorubicin (Adriamycin) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). We carried out whole-exome sequencing on collected tumor samples and matched leukocyte DNA from these patients. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. Results: In general, median progression-free survival (PFS) of the 10 confirmed Ewing sarcoma (with EWSR1-FLI1 fusion) patients was 10.5 months. We found that 60%, 30%, and 30% of patients had genetic variants (including mutation and copy number variation) in the three signaling pathways of cell cycle, WNT, and NOTCH, respectively. Their PFS was shorter than patients without these variants (log-rank test, p = 0.0345, 0.0053, and 0.0053, respectively). Median PFS was 7 vs 17 months in cell cycle pathway (the former with variants and the latter without variants), 5 vs 14 months in WNT pathway, and 5 vs 14 months in NOTCH pathway. However, there was no difference in PFS between patients with and without variants in other pathways (including TP53, RTK-RAS, MYC, DDR, PI3K) (log-rank test, p＞0.05). Conclusions: We found that the variants in cell cycle, WNT and NOTCH signaling pathway were associated with poor prognosis of Ewing sarcoma. This study provides important molecular markers for risk stratification in patients with Ewing sarcoma, which may provide insights into later clinical trials.
Clinical and time-related predictors of sepsis in patients with obstructive uropathy due to ureteral stones in the emergency setting
Authors: C. Bebi, M. Malfatto, G. Lucignani, M. Turetti, F. Ripa, C. Silvani, L. Rocchini, M.G. Spinelli, E. De Lorenzis, G. Albo, E. Montanari, L. Boeri
Journal: European Urology (2022)
Asymptomatic bacteriuria in candidates for active treatment of renal stones: Results from an international multicentric study on more than 2600 patients
Authors: T. Calcagnile, M.C. Sighinolfi, B. Rocco, P. Oltolina, S. Di Bari, S. Kaleci, R. Galli, P. Curti, L. Schips, P. Ditonno, L. Villa, S. Ferretti, F. Bergamaschi, G. Bozzini, A. Zoeir, A. El Sherbiny, A. Frattini, P. Fedelini, Z. Okhunov, A. Tubaro, J. Landman, S. Puliatti, G. Bianchi, S. Micali
Journal: European Urology (2022)
Preclinical anti-tumor activity of small-molecule oral PD-L1 checkpoint inhibitors.
Authors: Emily P. Thi, Andrew G. Cole, Gavin Heffernan, Christina L. Iott, Seyma Ozturk, Sharie C. Ganchua, Dan Nguyen, Ingrid Graves, Jorge G. Quintero, Kim Stever, Kristi Fan, Vijay Ahuja, Steven G. Kultgen, Maria Shubina, Boya Liu, Sunny Tang, Troy Harasym, Angela M. Lam, Michael J. Sofia
Journal: Journal of Clinical Oncology (2022)

e14558 Background: The PD-1/PD-L1 checkpoint axis is a validated target in oncology, and immunotherapy with antibody approaches have proven efficacy across various tumor types. Oral small-molecule inhibitors of PD-L1 may offer advantages over antibody approaches by enabling tunable on-target engagement and the potential for better tissue penetration and improved efficacy. Here we report the preclinical in vitro activity of small-molecule inhibitors of PD-L1 possessing a novel mechanism of action, favorable pharmacokinetics, and demonstrated in vivo efficacy in a mouse colon adenocarcinoma model. Methods: In vitro activity was assessed in a Jurkat T cell NFAT reporter assay and PD-L1 reduction was confirmed in CHO-K1 cells expressing human PD-L1 (CHO-K1-hPD-L1) and in peripheral blood mononuclear cells (PBMCs) from healthy donors. T cell activation assays were conducted with PBMCs from healthy donors. Non-specific cytokine release was evaluated in human whole blood. Pharmacokinetic (PK) evaluations were conducted in rodents and non-human primates (NHP). In vivo efficacy was evaluated in an MC38 tumor humanized PD-L1 and PD-1 mouse model. Results: Small-molecule inhibitors of PD-L1 were able to disrupt PD-1:PD-L1 and PD-L1:CD80 interactions through the reduction of PD-L1 expression on the cell surface via a novel internalization mechanism, resulting in PD-L1 degradation (EC 50s ranged from 1.9 – 24 nM in CHO-K1-hPD-L1 and primary human myeloid cells). Lead PD-L1 inhibitors mediated potent activation of T cells in a NFAT reporter assay (EC 50s of 13 and 18 nM) as well as dose responsive elevations in IL-2 production in human PBMCs stimulated with staphylococcal enterotoxin B. Compound treatment did not elicit non-specific cytokine release in human whole blood, supportive of favorable immune safety. PK profiles showed low systemic clearance in rodents and NHP. In an MC38 tumor model, once daily oral administration of compounds at 3, 10, and 30 mg/kg resulted in dose responsive tumor reduction that was associated with T cell activation and infiltration into tumors. Conclusions: Oral small-molecule PD-L1 inhibitors possessing a novel mechanism of action and the ability to mediate T cell activation in primary human immune cell types were identified. These compounds display in vivo anti-tumor efficacy comparable to anti-PD-L1 antibody and possess favorable preclinical profiles for further development, with the potential for all-oral treatment regimens for oncology.
Increased risk of venous thrombosis in breast cancer patients receiving chemotherapy treatment after COVID-19.
Authors: Tatiana V. Ausheva, Oksana V. Katelnitskaya, Oleg I. Kit, Elena M. Frantsiyants, Liubov Yu Vladimirova, Viktoria R. Zakharchenko, Irina V. Kaplieva, Iuliana S. Shatova, Anna Yu Ardzha
Journal: Journal of Clinical Oncology (2022)

e24106 Background: Immune suppression and coagulopathy development in cancer patients receiving chemotherapy determines a high incidence of complications, including venous thrombosis, and mortality from COVID-19 infection. There are still no explicit data on managing cancer patients when anticancer treatment is resumed after coronavirus disease. According to clinical guidelines for the prevention of venous thromboembolic complications in cancer patients receiving chemotherapy, patients with breast cancer are classified as having a low risk of these complications and do not require prophylactic anticoagulation. The purpose of this study was to assess the parameters of the blood coagulation system and the frequency of venous thrombosis in breast cancer patients with chemotherapy resumption after coronavirus disease. Methods: The study included 30 patients receiving anticancer medical therapy for breast cancer after COVID-19. Anticancer treatment was resumed no earlier than 4 weeks after clinical recovery, absence of SARS-CoV-2 RNAs in nasopharyngeal swabs, infiltrative lung damage according to a chest CT scan, exclusion of venous thrombosis by a lower extremity venous ultrasound. Control group included 20 breast cancer patients without a history of COVID-19. Stage I tumors were registered in 26.6% in the main group vs 15% controls; II - 40% vs 60%; III - 20% vs 15%. Some patients were diagnosed with distant metastases (stage IV- 13.3% vs 10%). Results: Initially, before chemotherapy resumption in the main group, half of the patients had elevated levels of fibrinogen and D-dimer compared with the control group (66.7% vs. 35%, p &gt; 0.05). After a cycle of chemotherapy, a significant difference in the coagulation system parameters was noted (73.3% vs 30%). A lower extremity venous ultrasound after the end of the therapy cycle in the main group showed venous thrombosis in 3 patients (catheter-related n = 2, distal vein thrombosis of the lower extremities n = 1), while no venous thrombotic complications were detected in the control group (10% vs. 0%). Conclusions: Breast cancer patients after coronavirus disease 2019 have hemostasis abnormalities and higher risk of venous thrombosis, and the resumption of anticancer treatment increases the incidence of thrombotic complications. COVID-19 should be considered an additional risk factor of venous thrombosis in cancer patients and requires reconsideration of indications for prophylactic anticoagulation when resuming anticancer treatment for patients with breast cancer.